The Bureau of National Affairs reports: "Just months after a groundbreaking
blood pressure study made headlines across the nation, a principal investigator
in the trial and his team have been sued in connection with the death
of a 60-year-old participant." (Scheer v. Burke, Pa. Ct. complaint filed
by attorney Alan Milltein on July 10).

The suit alleges that the dangers of the trial were concealed to convince
her husband to sign up. The suit further alleges that the researchers
did not follow the study rules once he was enrolled, and that the vasodilator
hydralazine, one of the other drugs used in the experiment, was misused
and ultimately killed Scott Scheer.

The multi-site ALLHAT experiment involved 10,300 patients. It found
strong evidence that low-cost, generic diuretics were more effective
than expensive, brand-name calcium channel blockers and ACE inhibitors
in lowering blood pressure and preventing heart attacks and strokes."
It was hailed by the medical establishment as "one of the most important
trials of antihypertensive therapy" in medical history.

But the experiment was the subject of a federal investigation by the
Office of Human Research Protection (OHRP) which found that the IRB
lacked sufficient information to justify its approval; that informed
consent documents failed to describe the foreseeable risks--such as
the risk of hydralazine-induced lupus; and that the potential benefits
were overstated; misleading patients into becoming subjects.

The ALLHAT patient brochure stated: "if you agree with us [and participate
in the ALLHAT trial], we promise to make every effort to safeguard your
welfare and provide the best possible care for your high blood pressure
and high cholesterol."

This is an example of how patients are being misled into believing
that experimental treatment in the context of research is therapeutic
and in their "best interest." In fact, within the research context,
patients are randomized to treatments that may be against their best
interest. In clinical practice, treatment is selected because it is
intended to serve the individual patient's best interest.

This case is yet another example of systemic failure by the current
research protection system—in particular, failure by the authorized
IRBs who are responsible for ensuring that (a) human subjects are protected
from harmful experiments, and (b) ensuring that the recruitment process
and informed consent documents comply fully with federal regulations
and full disclosure requirements. IRBs are empowered to evaluate the
scientific and ethical justification of research prior to approval.
IRBs are also responsible for monitoring adverse effects that may require
a re-assessment of the risks.

It is unfortunate IRBs are taking their cue from the major stakeholders
of the medical research community, and have not yet owned up to their
responsibility and the significance of their failure—as documented by
OHRP-- to protect research subjects. A culture of avoidance reigns even
as an embarrassing cascade of public disclosures reveal that IRBs across
the nation are failing to prevent research abuses at their institutions.

The most recent controversy surrounding two radical ARDSNetwork experiments
that violated the ethical standards set forth in the Declaration of
Helsinki: "The benefits, risks, burdens and effectiveness of a new method
should be tested against those of the best current prophylactic, diagnostic,
and therapeutic methods." [Article 29]

Of note: for well over a year, almost all AHRP Infomails have been
blocked from the IRB Forum, a discussion group comprising about 3,000
gatekeepers of research involving human subjects. Members of the IRB
Forum include professional IRB members from academic and commercial
research review committees, public officials, and a few non-affiliated
individuals. The Forum is supported by the University of Pennsylvania).

Most notably, the censored AHRP Infomails relate to research abuses,
harm to human subjects, and federal investigations. Indeed, information
about federal investigations and determinations--by OHRP and the FDA--
have rarely make it through the listserv for discussion. Indeed, there
has been little if any discussion on the IRB Forum about the ARDSNetwork
debacle--not about IRB approved consent failure to disclose the essential
risks, or failure to obtain legally valid consent; not about research
designs that increase risk of death for subjects, not about the ethics
of withdrawing critically ill patients from best standard of individualized
care and abruptly randomizing them to rarely used, experimental methods--independent
of patient need; not about the failure to systematically monitor mortality
rate during the trial-- to avoid preventable deaths.

Who, if not the federally authorized, professional IRB community should
be discussing these issues?

~~~~~~~~~~~~~
Below two articles from BNA's Medical Research Law & Policy Report:

ALLHAT Team Sued for Death of Subject;
Lack of Informed Consent, Negligence Cited

By M. Alexander Otto

Just months after a groundbreaking blood pressure study made headlines
across the nation, a principal investigator in the trial and his team
have been sued in connection with the death of a 60-year-old participant
(Scheer v. Burke, Pa. Ct. Com. Pl., number not available, complaint
filed 7/10/03). The widow of Dr. R. Scott Scheer July 10 sued Dr. James
F. Burke, the principal investigator of the Antihypertensive and Lipid
Lowering Treatment to Prevent Heart Attack Clinical Trial (ALLHAT) at
Lankenau Hospital in Wynnewood, Pa. Scheer died July 15, 2001, following
three-and-one-half years in the trial. The 10,300-patient, nationwide
ALLHAT grabbed headlines in December 2002 for providing strong evidence
that low-cost, generic diuretics were more effective than expensive,
brand-name calcium channel blockers and ACE inhibitors in lowering blood
pressure and preventing heart attacks and strokes. A Dec. 14, 2002,
Journal of the American Medical Association editorial declared ALLHAT
"one of the most important trials of antihypertensive therapy" in medical
history. But in her lawsuit, which was filed by attorney Alan C. Milstein,
Beverly H. Scheer alleged the ALLHAT team at Lankenau concealed the
dangers of the trial to convince her husband to sign up and did not
follow the study rules once he was enrolled. Misuse of the vasodilator
hydralazine, one of the other drugs used in the study, ultimately killed
Scott Scheer, the suit alleged. Scheer was a consulting radiologist
before he enrolled in ALLHAT.

Suit Follows OHRP Determination Letter

The federal Office for Human Research Protections found similar problems
in a November 2002 determination letter to the hospital. Patients were
not told of "any reasonably foreseeable risks and discomforts," including
the risk of serious hydralazine side effects, OHRP said. Lankenau's
institutional review board failed to update doses, informed consent
forms, and eligibility requirements when other study centers made changes,
and adverse events were not reported fast enough (1 MRLR 571, 12/4/02
). In August 2002, Kristina Borror, director of the OHRP Division of
Compliance Oversight, questioned how randomized subjects could be guaranteed
the "best possible care," as the consent form Scheer signed promised,
according to the complaint. Lankenau also promised potential subjects
the study "would help people like you ... lead more productive and longer
lives." JAMA reported that patients who got the calcium channel blocker
had a 38 percent increase in heart failure compared to the diuretic
group. Milstein, who practices with Sherman, Silverstein, Kohl, Rose
& Podolsky in Pennsauken, N.J., told BNA he was aware of the determination
letter when he filed, and that Beverly Scheer sought out his help. He
plans no additional ALLHAT lawsuits are planned at present. OHRP told
Lankenau it was satisfied with the hospital's corrective action plan
in a January 2003 follow-up letter (2 MRLR 69, 1/15/03 ). Burke's attorney,
Judy Mackarey, with Mackarey, Sunstein, Murphy & Davidson, Philadelphia,
had no comment pending review of the complaint.

Drug-Induced Lupus.

Scheer developed soft tissue swelling (edema) during the trial, but
Dr. Michael J. Duzy, the co-defendant who cared for Scheer, continued
to increase the dose of the blinded drug--which turned out to be the
calcium channel blocker, a known cause of edema--without investigating,
the lawsuit alleged. He then prescribed hydralazine, another edema-causing
drug, in response to a slight blood pressure increase in 1999. Lankenau's
ALLHAT patients never were told of the risk of edema, which can cause
permanent tissue damage, venous insufficiency, and death from blood
clots or bleeding, according to the complaint. The swelling worsened
and Scheer developed lupus--another side effect of hydralazine--in 2000,
but was kept on the drug until days before his death in July 200. He
also developed an abnormal electrocardiogram, muscle pain, and cataracts,
all of which were likely caused by study drugs but either went unreported
or uninvestigated in violation of ALLHAT protocols, the complaint alleged.
Scheer should have been pulled from the trial when the lupus progressed
to kidney damage, an ALLHAT endpoint, but he was not, the suit stated.
The radiologist was killed by a blood clot in his lungs, "a consequence
of drug induced lupus and end-stage rapidly progressing [kidney damage]
brought on by the continued ingestion of hydralazine," the complaint
explained. Scheer and other Lankenau patients were not told their blood
pressure would be treated experimentally rather than according to medical
standards that dictate starting patients on a diuretic and beta-blocker,
the complaint said. Scheer rated his health as "very good," a 90 on
a 100-point scale, just before entering the trial. The lawsuit seeks
damages in excess of $50,000 on each of seven counts including wrongful
death, lack of informed consent/battery, common law fraud/intentional
misrepresentation, negligence on the part of the Lankenau IRB, and breach
of fiduciary duty. In addition to Burke and Duzy, Lankenau Hospital,
parent company Main Line Hospitals Inc., and the Main Line IRB are among
the named defendants. Milstein understands the value of ALLHAT, but
said researchers need to "do what you say you are going to do; give
everyone care at least as good as the best standard care; and tell [subjects]
what drugs are in the study, when they will be administered, and what
the risks might be." The ALLHAT lawsuit and a separate complaint filed
against Genentech Inc. are the latest in a string of suits Milstein
has brought on behalf of patients injured in medical studies and their
relatives (see related item in the News section ). He first won fame
as a human subject plaintiff's attorney by representing the family of
Jesse Gelsinger, an 18-year-old killed in a University of Pennsylvania
gene therapy experiment in 1999. The school settled for an estimated
$10 million.

A controversial, multi-site acute respiratory distress syndrome (ARDS)
trial can resume, but only after informed consent forms are rewritten
to provide more information and institutional review boards re-review
the study in light of additional information, the Department of Health
and Human Services Office for Human Research Protections said July 3
in a letter to three of the several universities involved in the project.

The trial compares liberal versus conservative fluid replacement in
patients with the often-fatal lung condition. The National Institutes
of Health, which is funding the experiment, halted the trial in July
2002 after a five-member review panel concluded ARDSnet, a consortium
of pulmonary and critical care specialists at 24 hospitals in the United
States, used an invalid control and inadequate patient protections in
an earlier trial comparing ventilator tidal volumes (1 MRLR 428, 10/2/02).

About 400 patients were enrolled at the time with another 600 planned.
The 19 study centers and 40 affiliated hospitals participating in the
trial expect to resume enrollment in about a month, the time investigators
say they will need to address OHRP's concerns, said Dr. Herbert P. Wiedemann,
chairman of the Cleveland Clinic's Department of Pulmonary and Critical
Care Medicine and study chair of the fluid replacement trial.

OHRP said July 3 that ARDSnet researchers did not give IRBs enough
information in both the fluid replacement and ventilator trials. Among
the cited deficiencies, investigators never explained how or why they
chose to compare two experimental treatments, instead of an experimental
procedure against a standard one. They also did not inform board members
about standard treatments used in the their own hospitals, the letter
said.

Patients were not told they would be randomized to experimental treatments
and could die as a result, nor were they told they could choose alternative,
standard-of-care therapy, OHRP said. The fluid replacement trial must
be re-reviewed and consent forms reworked in light of such findings,
the office said. A team of eight consultants helped OHRP reach its conclusions,
according to the letter. OHRP Seeks Bioethicist Help. OHRP acknowledged
that, until the ARDSnet studies, there was no universally applied standard
ventilator tidal-volume setting for acute lung injury and ARDS patients.
Decisions were made based on best clinical judgment. The office twice
in its letter asked the scientific and bioethics communities for help
in determining how ethically to compare treatments when no true standard
exists, commenting that "the interests of future human subjects would
be served best by further discussion" of the issue. The office said
one approach might be to rely on local standards if universal standards
are lacking.

Patient advocate Vera Sharav, founder of the Alliance for Human Research
Protection, said the July 3 letter vindicated her concerns. "You cannot
bypass standard of care and expose patients to two experimental treatments
when the risk is death," she told BNA.

A better way would be to compare an experimental group against patients
whose ARDS treatments are customized to their individual needs, as is
usually the case. Patients fared worse when plucked from individualized
care and randomly assigned tidal volumes in the ARDSnet trial that studied
tidal volumes, she said, adding that the group's work remains "a scandal."

However, Wiedemann said ARDSnet investigators read an entirely different
message into OHRP's letter. By allowing the fluid management trial to
resume, the office said it is permissible to compare two experimental
treatments within the range of those used when a standard approach is
lacking, the Cleveland Clinic researcher said.

OHRP "has ruled the trial does not violate federal law. This is huge,
in our view, and a major validation of our approach. The design of our
trial was not faulted, and the trial can resume with the exact same
design we started with," he said. In the April 3 issue of The New England
Journal of Medicine, two ARDSnet researchers criticized OHRP for its
pursuit of their work, claiming the office had no authority to question
the scientific merits of any study, only its adherence to federal study
safety rules (2 MRLR 340, 5/7/03). OHRP had questioned whether comparing
experimental treatments had value in a December 2002 determination letter
demanding to review ARDSnet patient records. By M. Alexander Otto

Copyright 2003, The Bureau of National Affairs, Inc., Washington,
D.C.